4FLP

Crystal Structure of the first bromodomain of human BRDT in complex with the inhibitor JQ1

Summary for 4FLP

• Entry DOI: 10.2210/pdb4flp/pdb
• Related: 2RFJ
• Descriptor: Bromodomain testis-specific protein, (6S)-6-(2-tert-butoxy-2-oxoethyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6,7-dihydrothieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-10-ium, POTASSIUM ION, ... (4 entities in total)
• Functional Keywords: brdt, bromodomain containing protein testis specific, nucleus, transcription, transcription regulation, structural genomics consortium, sgc, bromodomain, transcription regulator-inhibitor complex, transcription regulator/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (Probable): Q58F21
• Total number of polymer chains: 2
• Total formula weight: 29287.94

Authors

Filippakopoulos, P.,Picaud, S.,Qi, J.,Felletar, I.,Canning, P.,Muniz, J.,von Delft, F.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.,Bradner, J.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2012-06-15, release date: 2012-07-11, Last modification date: 2023-09-13)

Primary citation

Matzuk, M.M.,McKeown, M.R.,Filippakopoulos, P.,Li, Q.,Ma, L.,Agno, J.E.,Lemieux, M.E.,Picaud, S.,Yu, R.N.,Qi, J.,Knapp, S.,Bradner, J.E.
Small-Molecule Inhibition of BRDT for Male Contraception.
Cell(Cambridge,Mass.), 150:673-684, 2012

PubMed Abstract: A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood:testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception.

PubMed: 22901802
DOI: 10.1016/j.cell.2012.06.045

Experimental method

X-RAY DIFFRACTION (2.23 Å)